rs1132200

Positions:

• chr3-119431989-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018266.3(TMEM39A):​c.1459G>A​(p.Ala487Thr) variant causes a missense change. The variant allele was found at a frequency of 0.146 in 1,581,760 control chromosomes in the GnomAD database, including 18,235 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1171 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17064 hom.)
• Consequence: TMEM39A NM_018266.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.42

Genes affected

TMEM39A (HGNC:25600): (transmembrane protein 39A) Involved in negative regulation of autophagosome assembly; negative regulation of autophagosome maturation; and positive regulation of viral genome replication. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013440847).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM39A	NM_018266.3	c.1459G>A	p.Ala487Thr	missense_variant	9/9	ENST00000319172.10	NP_060736.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM39A	ENST00000319172.10	c.1459G>A	p.Ala487Thr	missense_variant	9/9	1	NM_018266.3	ENSP00000326063	P1
TMEM39A	ENST00000438581.6	c.*1127G>A		3_prime_UTR_variant, NMD_transcript_variant	10/10	1		ENSP00000402149
TMEM39A	ENST00000473684.5	c.*497G>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	5		ENSP00000420432

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16612 AN: 151852 Hom.: 1172 Cov.: 32

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.0892

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0769

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.121 AC: 29415 AN: 242486 Hom.: 2068 AF XY: 0.127 AC XY: 16618 AN XY: 131342

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.0642

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0838

Gnomad SAS exome AF: 0.132

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.150 AC: 214166 AN: 1429790 Hom.: 17064 Cov.: 30 AF XY: 0.150 AC XY: 106524 AN XY: 709772

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.0690

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.0941

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.109 AC: 16612 AN: 151970 Hom.: 1171 Cov.: 32 AF XY: 0.107 AC XY: 7968 AN XY: 74276

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.0891

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.0771

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.118

Alfa AF: 0.146 Hom.: 3048

Bravo AF: 0.103

TwinsUK AF: 0.165 AC: 610

ALSPAC AF: 0.149 AC: 574

ESP6500AA AF: 0.0356 AC: 157

ESP6500EA AF: 0.160 AC: 1372

ExAC AF: 0.121 AC: 14723

Asia WGS AF: 0.0850 AC: 295 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.026	P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.10
Sift	Benign	0.033	D
Sift4G	Benign	0.086	T
Polyphen		0.043	B
Vest4		0.097
MPC		0.37
ClinPred		0.0073	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1132200; hg19: chr3-119150836; COSMIC: COSV59900341; COSMIC: COSV59900341;